The 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria, including a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on specific considerations for the different types of loss of function variants, nor did it provide decision‐making pathways assimilating information about variant type, its location, or any additional evidence for the likelihood of a true null effect. Furthermore, this guideline did not take into account the relative strengths for each evidence type and the final outcome of their combinations with respect to PVS1 strength. Finally, criteria specifying the genes for which PVS1 can be applied are still missing. Here, as part of the ClinGen Sequence Variant Interpretation (SVI) Workgroup's goal of refining ACMG/AMP criteria, we provide recommendations for applying the PVS1 criterion using detailed guidance addressing the above‐mentioned gaps. Evaluation of the refined criterion by seven disease‐specific groups using heterogeneous types of loss of function variants (n = 56) showed 89% agreement with the new recommendation, while discrepancies in six variants (11%) were appropriately due to disease‐specific refinements. Our recommendations will facilitate consistent and accurate interpretation of predicted loss of function variants. We provide guidance for PVS1 usage that takes into consideration all aspects of putative loss of function (LoF) variants, including type, location, and annotation, and the disease mechanism of the genes they affect. We demonstrate how the combination of these variant and gene attributes can lead to varied PVS1 strength levels. Finally, we evaluate the refined criterion using > 50 LoF variants in several genes and diseases.